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Abstract
The end replication problem, which occurs in normal somatic cells inducing replicative senescence, is solved in most cancer cells by activating telomerase. The activity of telomerase is highly associated with carcinogenesis which makes the enzyme an attractive biomarker in cancer diagnosis and treatment. The indole alkaloid harmine has multiple pharmacological properties including DNA intercalation which can lead to frame shift mutations. In this study, harmine was applied to human breast cancer MCF-7 cells. Its activity towards telomerase was analyzed by utilizing the telomeric repeat amplification protocol (TRAP). Our data indicate that harmine exhibits a pronounced cytotoxicity and induces an anti-proliferation state in MCF-7 cells which is accompanied by a significant inhibition of telomerase activity and an induction of an accelerated senescence phenotype by over-expressing elements of the p53/p21 pathway.
Highlights
The end replication problem results in a continuous shortening of each end of a chromosome
Most cancer cells can conquer this obstacle because their telomerase, a ribonucleoprotein that replicates telomere sequences at each cell division, remains active
Telomerase is highly associated with carcinogenesis. It is detectable in 85–90% of human cancers and over 70% of immortalized human cell lines (Kim et al, 1994; Shay & Wright, 1996a; Shay & Wright, 1996b), whereas it is undetectable in non-transformed somatic cells
Summary
The end replication problem results in a continuous shortening of each end of a chromosome. In most somatic cells the shortened fragments cannot be compensated. Cells stop dividing when telomeres reach a critical length and replicative senescence is initiated . Most cancer cells can conquer this obstacle because their telomerase, a ribonucleoprotein that replicates telomere sequences at each cell division, remains active. It is detectable in 85–90% of human cancers and over 70% of immortalized human cell lines (Kim et al, 1994; Shay & Wright, 1996a; Shay & Wright, 1996b), whereas it is undetectable in non-transformed somatic cells. Telomerase is an attractive target for the development of anti-cancer drugs
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